ABSTRACT
Objective: To investigate the applicability of the spray-dried microspheres of vinyl pyrrolidone/vinyl acetate copolymer VA64-Soluplus for inclusion of cinnamon oil (CO) and compare with traditional inclusion technology of β-cyclodextrin. Methods: HPLC was used to determine the encapsulation rate of inclusion complex. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) were used to characterize the inclusion complex; The dissolution and stability of the inclusion complex was investigated by in vitro release test and accelerated stability test; The pharmacokinetic and analgesic efficacy tests were used to examine the bioavailability and efficacy of the inclusion complex. Results: The encapsulation rate of microsphere inclusion complex and β-cyclodextrin inclusion complex was (98.38 ± 0.30)% and (86.51 ± 0.52)%, respectively. Observation of the inclusion complex under TEM showed a uniform spherical-like structure with uniform dispersion; Observation under SEM showed that the inclusion complex was spherical with a concave surface; The endothermic peak of volatile oil of cinnamon in DSC and the diffraction peak in XRD disappeared. The cinnamon volatile oil was dispersed in theinclusion complex in the form of non-aggregation; The cumulative release rates of cinnamon volatile oil, microsphere inclusion complex and β-cyclodextrin inclusion complex in in vitro dissolution experiments were 97.05%, 93.36% and 80.26%, respectively; Accelerated stability test at 60 ℃ showed that the loss rate of volatile oil of microsphere inclusion complex was significantly lower than that of cinnamon volatile oil and β-cyclodextrin inclusion complex; Pharmacokinetics showed that the AUC0-∞ of cinnamon essential oil, microsphere inclusion complex and β-cyclodextrin inclusion complex were basically the same; Pharmacodynamics showed that the analgesic rates of cinnamon volatile oil in the three groups were 53.0%, 47.5% and 21.1%, respectively. Conclusion: The stability of cinnamon volatile oil was enhanced by the combination of spray-dried microspheres of vinyl pyrrolidone/vinyl acetate copolymer VA64-Soluplus. The in vitro release, bioavailability and analgesic efficacy of microsphere were basically consistent with the volatile oil of cinnamon volatile oil, and it was superior to the inclusion compound of β-cyclodextrin. The vinyl pyrrolidone/vinyl acetate copolymer VA64-Soluplus microsphere inclusion compound had better water solubility. This study provides a new method for the inclusion of volatile oil.
ABSTRACT
Objective: To investigate the effect of three types of precipitation inhibitors (PPI) HPMC K4M, HPMC AS MG and Soluplus on the pH-induced supersaturated phase behavior of dl-tetrahydropalmatine (dl-THP) at oral clinical doses. Methods: dl-THP pH solubility phase diagram and desaturation curve during pH-shift were drawn, and the solubility phase diagram was used to support dl-THP phase behavior. Area under the concentration-time curve and supersaturation ratio were used to analyze the effect of PPI on the phase behavior of dl-THP; Polarized light microscope and differential scanning calorimetry were used to analyze the precipitation properties. Results: Under the clinical dosage, the maximum supersaturation of dl-THP during the pH-shift was 3.93, and the supersaturation was lost over time; HPMC K4M, HPMC AS MG, and Soluplus could all maintain the supersaturation within 180 minutes during the pH-shift dissolution. HPMC K4M, HPMC AS MG, and Soluplus maintained supersaturation levels of 1.19, 1.89 and 1.36 respectively at a concentration of 5%, 1.30, 2.35 and 1.86 at a concentration of 20%, and 1.30, 2.60 and 2.07 at a concentration of 50%. Polarized light microscopy and differential scanning calorimetry results showed that crystalline precipitation occurred. Conclusion: All precipitation inhibitors can improve the pH-induced supersaturated phase behavior of tetrahydropalmatine, and this improvement behavior varies with the type and concentration of precipitation inhibitors. HPMC AS MG has the best effect.
ABSTRACT
@#Solid dispersions of the insoluble compound CHMFL-KIT-110 were prepared by solvent method with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus),Poloxamer 407,PEG 6000,Copovidone (Kollidon VA64) as carriers and SLS,Tween 80,Cremophor RH40 as solubilizers. The optimal formulation was screened and obtained with dynamic solubilities and supersaturation performances as indexes. The final product was characterized by Fourier transform infrared (FT-IR),differential thermal analysis (DTA) and X-ray powder diffraction (XRPD). The stability and pharmacokinetic behavior in rats were also investigated. Results suggested that when the weight ratio of CHMFL-KIT-110/Soluplus/SLS was 1∶4∶0.5,dynamic solubility of the solid dispersions was significantly improved with no recrystallization. In the accelerated condition (40 °C,75% RH) for 30 days,CHMFL-KIT-110 in the solid dispersions was still amorphous with no crystal observed. The results of pharmacokinetics in rats showed that the cmax and AUC0→t of CHMFL-KIT-110 solid dispersions were 373.1 times and 358.7 times higher than those of free drugs,respectively. These results help to understand the formulation development and clinical practice of CHMFL-KIT-110.
ABSTRACT
The present work aims to enhance the water solubility of nimodipine, a hydrophobic drug, using a solid dispersion(SD) technique. Soluplus® as a novel hydrophilic polymeric carrier was used. Nimodipine-Soluplus® SDs (1:10) wereprepared by impregnation technique using supercritical fluid technology (SCF) and compared with the ones whichwere prepared by conventional hot-melt (HM) method. The solubility and the in vitro release study of the raw drug,solid dispersions, and the corresponding physical mixtures were characterized and compared. The prepared SD bySCF technology showed 77-fold increase in nimodipine solubility, in comparison to 48-fold increase when preparedby HM and 7.7-fold when physically mixed. Moreover, they showed the highest percentage of nimodipine cumulativerelease within the studied period. The results were confirmed the amorphous transfer of the drug into the polymermatrix which was assured by the powder X-ray diffraction and the thermal analysis. In addition to the hydrogen bondformation between nimodipine and Soluplus®, which was evident in the FTIR spectra; A weakening of peak related tonimodipine N–H stretching and C=O of the ester group. Nimodipine solid dispersion with Soluplus® using the SCFtechnology might represent a promising formulation for nimodipine to enhance its oral bioavailability
ABSTRACT
Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system (SDDS). In this study, we reported a complex system of Soluplus-Copovidone (Soluplus-PVPVA) loaded with the model drug silybin (SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus-PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus-PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution the adsorption of PVPVA on the hydrophilic-hydrophobic interface of the Soluplus micelle, and the Soluplus-PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus-PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.
ABSTRACT
OBJECTIVE: To develop an analytical method for the quantification of scopoletin (Sco) and investigate the cellular uptake and metabolism of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (soluplus)-based Sco micelles (Sco-Ms) in Caco-2 cells, as well as exploring the possible mechanisms involved in the oral absorption of Sco-Ms.METHODS: Combined with enzymatic hydrolysis for pretreatment, a liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-MS/MS) method was developed for the quantification of Sco and its corresponding metabolite. Then, cellular uptake efficiency and metabolic rate of Sco were calculated.RESULTS: This method was proven to be linear over the concentration range of 5-1 000 ng•mL-1. Cellular uptake of Sco-Ms increased significantly compared with that of free Sco at various time points. Meanwhile, Sco-Ms inhibited the enzymatic degradation of Sco. Sco-Ms were primarily internalized into enterocytes via macropinocytosis and clathrin-dependent pathways.CONCLUSION: Enhanced cellular uptake and decreased metabolic rate are pivotal mechanisms by which Sco-Ms promotes oral absorption of Sco.
ABSTRACT
@#Aimed at developing new formulation, amorphous solid dispersion of itraconazole was prepared via hot-melt extrusion technology and compared with sporanox for improving its dissolution. According to the solubility parameter and glass transition temperature, Soluplus, Kollidon VA64, HPMCAS and Eudragit EPO were used as carriers. After screening the carriers by modulated temperature-differential scanning calorimetry(MT-DSC), the amorphous solid dispersion was prepared successfully and characterized by MT-DSC, polarized light microscope(PLM), X-ray powder diffraction(XRPD)and Fourier Transform InfraRed(FT-IR). Results suggested that the amorphous form of ITZ solid dispersion and whether the interaction between polymer and ITZ was appeared. Using 30% and 50% drug loading, solid dispersion were tested by in vitro dissolution and kinetic solubility tests. When using Soluplus(3 ∶7)as carrier and extrusion temperature of 170 ℃, dissolution rate of itraconazole was improved significantly compared to Sporanox. In 40 ℃, 75% RH condition, itraconazole in the solid dispersion was amorphous for 30 d with no crystal observed. MT-DSC indicated the molecular level miscibility between Soluplus and amorphous itraconazole was probably the main cause of solubilization. The result from this research help understanding the solublization of amorphous itraconazole and future formulation development.
ABSTRACT
OBJECTIVE: To examine the effects of TPGS 1000 and Soluplus on the transport of ginsenoside CK in Caco-2 cell model. METHODS: The effects of TPGS 1000 and Soluplus at different concentrations on ginsenoside CK were evaluated by using Caco-2 cell model. The concentration of ginsenoside CK in cell was examined by ultra high pressure liquid chromatography (UPLC) method. The apparent permeability coefficient (Papp) and the efflux ratio were calculated. RESULTS: When the proportion of ginsenoside CK to TPGS 1000 or Soluplus was 1:1, 1:3, and 1:9, the absorption of ginsenoside CK significantly increased. The efflux and efflux ratio both decreased significantly (P<0.05). TPGS 1000 had more significant promotion effect on the transport of ginsenoside CK than the same dose of soluplus at the same ratio (P<0.05). CONCLUSION: In Caco-2 cell model, both TPGS 1000 and Soluplus can significantly promote the absorption of ginsenoside CK.